Cardiac Mechanobiology in Physiology and Disease

Foreword
Contents
Cardiac Mechanoperception and Mechanotransduction: Mechanisms of Stretch Sensing in Cardiomyocytes and Implications for Cardio...
1 Introduction
2 The Z-Disc and Mechanotransduction
2.1 Strain Sensing and Mechanotransduction at the Sarcomeric Z-Disc/I-Band
2.2 The Z-Disc/I-Band Titin/MLP/TCAP Complex: Stretch Sensing Within Sarcomeric Borders
2.3 Calcineurin as Major Player in Cardiac Stress Signaling
2.4 N2B Titin Controlled Mechanosensing Hubs
3 Sensing of Mechanical Strain and Signal Transduction at the Center of the Sarcomere, the M-Band
4 Stretch Sensing Between Cardiomyocytes and the Extracellular Matrix via the Intercalated Discs and Costameres
4.1 The Extracellular Matrix: More Than Just Collagens
4.2 Stretch Transmission at Costameric Integrin-Talin-Vinculin Clutches
4.3 Stretch Signaling at Costameric Dystrophin Glycoprotein Complexes
5 Force Sensing and Transmission at Cell-Cell Contacts in the Heart
5.1 Stretch Signaling at Cardiac Desmosomes
6 Sarcolemmal Strain Sensing and Mechanoelectrical Feedback via Mechanosensitive Ion Channels
6.1 Mechanosensitive Transient Receptor Potential Channels (Polycystins) in the Heart
6.2 Other Mechanosensitive Calcium Channels in the Heart
6.3 Mechanosensitive Potassium Channels in the Heart
7 The Microtubule Network in Cardiomyocyte Stretch Sensing: More Than Just a Skeleton
7.1 Mechanotransduction at the Cardiomyocyte´s Nuclear Lamina
7.2 Mechanotransduction by Protein Complexes Within the Nuclear Envelope
8 Mechanotransduction and Mechanosensitive Gene Induction
9 Translational Perspectives
10 Conclusions
References
Mechanotransduction in Heart Development
1 Introduction
2 Forces and Mechanotransduction in Heart Development
3 Hemodynamic Influence on Cardiac Looping and Chamber Development
4 Chamber Development, Trabeculation, and Hemodynamic Conditions
5 Flow Forces Drive Outflow Tract Development
6 Role of Mechanical Forces in Valve Development
7 Conclusions
References
Mechanobiology of Cardiac Growth in Health and Disease
1 Molecular Control of Cardiac Mechanotransduction
2 Mechanical Regulation of Primary Cardiomyocyte Differentiation
3 Conclusions
References
The Role of Mechanosensitive Signaling Cascades in Repair and Fibrotic Remodeling of the Infarcted Heart
1 Introduction
2 The Functional Consequences of Myocardial Ischemia
3 The Phases of Infarct Healing
4 The Inflammatory Phase of Infarct Healing
5 The Proliferative Phase of Infarct Healing
6 Myofibroblasts: Central Effectors of Repair in the Infarcted Heart
7 The Mechanisms of Fibroblast and Myofibroblast Activation in the Infarcted Myocardium: From the Cell Surface to the Nucleus ...
7.1 Neurohumoral Pathways and the Renin-Angiotensin-Aldosterone System (RAAS)
7.2 The Role of Cytokines and Chemokines in Fibroblast Activation
7.3 The Role of TGF-β in the Activation of Infarct Myofibroblasts
7.4 Components of the Provisional Matrix as Regulators of Fibroblast Activation
7.5 Specialized Matrix Proteins Transduce Reparative and Fibrogenic Signals in the Infarcted Heart
7.6 Integrins
7.7 Mechanosensitive Ion Channels
7.8 Focal Adhesion Kinase (FAK)
7.9 MAPKs
7.10 The RhoA/ROCK Pathway
7.11 The YAP/TAZ Pathway in Mechanosensitive Activation of Fibroblasts
7.12 Mechanosensitive Activation of MRTF in Infarct Fibroblast Activation
8 The Extracellular Matrix in the Maturation Phase of Infarct Healing
9 Mechanical Stress May Play a Major Role in Mediating Adverse Remodeling in the Non-infarcted Myocardium
10 Translational Perspectives
10.1 Ventricular Unloading in Myocardial Infarction
10.2 Targeting Mechanosensitive Cascades to Improve Repair and to Attenuate Fibrotic Post-infarction Remodeling
11 Conclusions
References
Mechanobiology of Cardiac Fibroblasts in Cardiac Remodeling
1 Introduction
2 Overview of Cardiac Fibroblasts
2.1 Cardiac Fibroblasts in the Context of Cell and Tissue Development
2.2 Cardiac Fibroblasts in ECM Maintenance and Remodeling
2.3 Cardiac Fibroblasts in Vitro
3 Cardiac Fibroblasts Facilitate, and Respond to, Age-Dependent Alterations in Cardiac Mechanics
4 Mechanobiology of Fibroblasts in Cardiac Injury and Disease
5 CFs Role in Pathophysiology
5.1 Congenital Heart Disease
5.2 Pressure Overload
5.3 Hypertrophy
5.4 Myocardial Infarction and Heart Failure
6 Conclusions and Critical Outstanding Questions
References
Mechanobiology of Cardiac Remodelling in Cardiomyopathy
1 What Happens at the Cellular Level in Hypertrophic Cardiomyopathy (HCM) Versus Dilated Cardiomyopathy (DCM)?
2 Returning to Old Concepts: HCM Is a Disease of Force Production and DCM Is a Disease of Force Transmission?
3 The Intercalated Disc: The Epicentre for Postnatal Cardiomyocyte Growth and Maladaptive Mechanosignalling?
4 Mechanical Stress and Channel Regulation
5 How Are These Stress Signals Conveyed into Changes in Gene Expression?
6 Will the Future Bring Drugs That Interfere with Mechanosignalling?
7 Conclusion
References
Biophysical Stretch Induced Differentiation and Maturation of Induced Pluripotent Stem Cell-Derived Cardiomyocytes
1 Introduction
2 Changes in Cardiomyocyte Characteristics During Myocardial Development
2.1 Differences Between Native Myocardial and 2D-Cultured Cardiomyocytes
2.2 Cell Morphology
2.3 Electrical Signal Conduction
2.4 Metabolism
3 Biophysical Cues for iPSC-CM Maturation
3.1 Matrix Stiffness and Surface Topography in 2D-Culturing
3.2 3D-Culturing via Improved Scaffold Design
3.3 Mechanical Loading and Stretch
4 Underlying Mechanisms of Biomechanical Stimulation
5 Conclusion
References
Mechanical Considerations of Myocardial Tissue and Cardiac Regeneration
1 Current Regenerative Strategies Fail to Restore the Myocardial Mechanical Environment
2 Understanding the Multiscale Biomechanical Properties of the Myocardium
3 Mechanics-Based In Vitro Models to Understand Cardiac Behaviour at the Micro- and Mesoscale
3.1 Cardiac ECM Organisation
3.2 ECM Stiffness
3.3 Strain on Cells
3.4 Mechanoelectrical Feedback
3.5 Developing Integrated Models for Mechanical Consideration In Vitro
4 In Silico Models to Study the Mechanics of Myocardial Remodelling and Regeneration
5 Conclusion
References
Mechanobiology of Exercise-Induced Cardiac Remodeling in Health and Disease
1 Introduction
2 Cardiovascular Function During Exercise
3 The Athletic Heart
3.1 Structural Remodeling of the Left Ventricle
3.2 Right Ventricular Remodeling Among Athletes
3.3 The Impact of Exercise on the Interventricular Septum
3.4 Atrial Remodeling and the Risk of Atrial Fibrillation
4 Impact of Exercise on Ventricular Function
5 Variations in the Electrocardiogram Among Athletes
6 Inherited and Acquired Cardiomyopathies
6.1 Hypertrophic Cardiomyopathy
6.2 Dilated Cardiomyopathy
6.3 Arrhythmogenic Right Ventricular Cardiomyopathy
7 Conclusions
References
Cardiac Microvascular Endothelial Cells and Pressure Overload-Induced Cardiac Fibrosis
1 Introduction
2 Pressure Overload
3 Cardiac Fibrosis
4 Signalling Pathways in Cardiac Fibrosis
5 Cardiac Fibroblasts
6 Endothelial Cells
6.1 Macrovascular Versus Microvascular Endothelial Cells
6.2 Cardiac Microvascular Endothelial Cells
6.3 Effects of Pro-fibrotic Signals on Endothelial Cells
7 Anti-fibrotic Therapies
8 Conclusion(s)
References
Cellular and Subcellular Mechanisms of Ventricular Mechano-Arrhythmogenesis
1 The Cardiac Mechano-Electric Regulatory Loop
2 Clinical Evidence and Experimental Studies of Ventricular Mechano-Arrhythmogenesis
2.1 Clinical Evidence
2.2 Experimental Studies
3 Cellular and Subcellular Mechanisms of Ventricular Mechano-Arrhythmogenesis
3.1 Mechano-Sensitive Ion Channels
3.1.1 MSCNS
3.1.2 MSCK
3.2 Biophysical Signal Transmitters
3.3 Mechano-Sensitive Biochemical Signals
3.3.1 Mechano-Sensitive Ca2+ Handling
3.3.2 Mechano-Sensitive ROS Production
4 Ventricular Mechano-Arrhythmogenesis in Cardiac Disease
4.1 Acute Regional Myocardial Ischaemia
4.1.1 Metabolic, Electrophysiological and Ionic Changes
Hypoxia
Extracellular K+ Accumulation
Intracellular Acidosis
Electrophysiological Changes
Alterations in Ca2+ Handling
4.1.2 Stretch of Ischaemic Myocardium
4.1.3 Tissue-Level Considerations for Mechano-Arrhythmogenesis in Acute Regional Ischaemia
4.2 Chronic Hypertension
4.2.1 Structural Remodelling
Microtubule Network
Microtubule Post-Translational Modifications
4.2.2 Proposed Mechanisms of Mechano-Arrhythmogenesis in Hypertension
5 Conclusion
References
Computational Biomechanics of Ventricular Dyssynchrony and Resynchronization Therapy
1 Introduction
2 Modelling Anatomy
2.1 Geometry
2.2 Fibers
2.3 Scar
3 Clinical Measurements
3.1 Electrical Measurements
3.2 Functional Measurements
4 Electrophysiology Models
4.1 Models of Cardiac Electrophysiology
4.2 Purkinje System or Fast Endocardial Conduction?
4.3 Lead Optimization
4.4 ECG Simulations
5 Mechanical Models
5.1 Passive Mechanical Models
5.2 Electromechanics Modeling
5.3 Active Contraction Models and Mechano-Electric Feedback
5.4 Cardiac Myocyte Growth Models
5.5 Acute Hemodynamic Response
5.6 Lead Location Optimization
5.7 Device Setting Optimization
5.8 Multisite Pacing
5.9 Endocardial Pacing
5.10 His and Left Bundle Pacing
5.11 Limitations of Electromechanical Models
6 Circulatory Models
6.1 CircAdapt Model
6.2 TriSeg Model
6.3 MultiPatch Model
7 Challenges, Opportunities, and Future Directions
8 Conclusion
References
Therapeutic Innovations for Heart Failure
1 Basic Mechanisms of Heart Failure
2 Pharmacological Treatment of Heart Failure
3 Anti-inflammatory Therapy
4 Gene Therapy
5 RNA-Based Methods for Heart Failure
6 Conclusion and Future Perspectives
References